Sites and mechanisms of insulin resistance in nonobese, nondiabetic patients with chronic hepatitis C

Abstract

Chronic hepatitis C (CHC) has been associated with type 2 diabetes and insulin resistance, but the extent of impairment in insulin action, the target pathways involved, and the role of the virus per se have not been defined. In this study, we performed a euglycemic hyperinsulinemic clamp (1 mU ⅐ minute ؊1 ⅐ kg ؊1 ) coupled with infusion of tracers ([6,6-2 H 2 ]glucose, [ 2 H 5 ]glycerol) and indirect calorimetry in 14 patients with biopsy-proven CHC, who were selected not to have any features of the metabolic syndrome, and in seven healthy controls. We also measured liver expression of inflammatory cytokines/mediators and tested their association with the metabolic parameters. Compared to controls, in patients with CHC: (1) total glucose disposal (TGD) during the clamp was 25% lower (P ‫؍‬ 0.003) due to impaired glucose oxidation (P ‫؍‬ 0.0002), (2) basal endogenous glucose production (EGP) was 20% higher (P ‫؍‬ 0.011) and its suppression during the clamp was markedly reduced (P ‫؍‬ 0.007), and (3) glycerol appearance was not different in the basal state or during the clamp, but lipid oxidation was less suppressed by insulin (P ‫؍‬ 0.004). Lipid oxidation was higher in patients with CHC who had more steatosis and was directly related to EGP, TGD, and glucose oxidation. The decreased insulin-stimulated suppression of EGP was associated with increased hepatic suppressor of cytokine signaling 3 (SOCS3; P < 0.05) and interleukin-18 (P < 0.05) expression. T ype 2 diabetes (T2DM) is a frequent complication of hepatitis C virus (HCV) infection, second in prevalence only to cryoglobulinemia. The first report by Allison et al. 1 of an increased prevalence of T2DM in HCV-positive subjects with cirrhosis has been repeatedly confirmed also at earlier stages of liver disease. 2,3 In a large survey study, 3 HCV-positive subjects older than 40 years were three times more likely than HCV-negative controls to have diabetes. In a longitudinal study, the risk of developing diabetes was up to 12 times higher in patients who were HCV-positive than in the general population. 4 HCV is associated with insulin resistance (IR) also in nondiabetic patients. In a prospective study including 600 consecutive patients with chronic hepatitis C (CHC), 5 IR assessed using the Homeostasis Model Assessment of IR (HOMA-IR) was found in 32% of patients without diabetes and was associated with both the metabolic syndrome (MS) and with high serum HCV RNA levels, suggesting a possible interaction of viral replication with insulin action. The improvement of IR in

Risk Factors for Hepatocellular Carcinoma in India

“…54 Type II DM is common in Hepatitis C (HCV) infection as compared to the controls. 59 In India the prevalence of Figure 1 Hepatitis C and diabetes mellitus. 67 [(AFR, African; AMR, The Americas; EMR, Eastern Mediterranean; EUR, European; SEAR, South-East Asian; and WPR, Western Pacific), as defined in the GBD 2000 project.…”

Associations of chronic hepatitis C with metabolic and cardiac outcomes

“…Some of these mechanisms include direct interaction of HCV proteins with the hepatocyte insulin signalling cascade [6][7][8] or impairment of pancreatic b-cell function. 9 In addition, recent evidence suggests involvement of the striated muscle in the pathogenesis of IR in patients with CH-C. 10 The consequences of IR and DM in HCV-infected patients can be divided into those that affect liver disease outcomes and those affecting nonliver related outcomes. 11 HCV patients with DM or IR tend to have more advanced hepatic fibrosis, hepatocellular carcinoma and lower efficacy of treatment regimens.…”

Homeostasis model assessment of insulin resistance does not seem to predict response to telaprevir in chronic hepatitis C in the REALIZE trial

“…5,6,29 However, although SOCS-3 has been reportedly elevated in the liver of chronic hepatitis C patients with IR, 7 its role in reducing the response to therapy has been challenged by experimental 30 and clinical data. 31 A second hypothesis is based on data suggesting that high concentrations of insulin directly inhibit interferon alpha signaling, independently of SOCS-3.…”

“…2,3 Proposed mechanisms for HCV-related IR and diabetes mellitus include direct hepatic effects [4][5][6] and potential contributions from extrahepatic organs. 7,8 In HCV-infected patients, IR appears to influence disease progression and response to treatment with peginterferon alpha and ribavirin. 9,10 IR appears to be associated with a lower rate of sustained virologic response (SVR) in patients receiving peginterferon alpha and ribavirin.…”